The antipsychotic actions of classic neuroleptics revolutionized the therapy of schizophrenia, but their use has been impeded by side effects such as extrapyramidal symptoms, tardive dyskinesia, a high incidence of non-responders, and the failure of negative symptoms such as apathy to respond. The atypical antipsychotic drugs (AAPDs), pioneered by clozapine, represent an important advance improving negative symptoms, benefiting patients who do not respond to the typical drugs, and displaying fewer side effects (1-5). A major limitation of AAPDs is pronounced weight gain predominantly mediated by increased food intake (6-10).
Weight gain elicited by AAPDs is primarily related to increased food intake though there may also be metabolic alterations (12-14). To directly address central systems that mediate appetite and weight gain we have explored phosphorylation of hypothalamic AMPK, which activates the enzyme (15, 16). Hypothalamic AMPK has been linked to the regulation of food intake (11). In the periphery, AMPK activation is associated with decreased lipid formation, as AMPK phosphorylates acetyl-CoA carboxylase (ACC) inhibiting the generation of malonyl-CoA. Malonyl-CoA is a substrate for fatty acid synthase so that inhibition of ACC diminishes formation of fatty acids and lipid (15-17). In the hypothalamus, AMPK acts in a seemingly reciprocal fashion to regulate food intake (16, 18-20). Kahn and collaborators (11) showed that AMPK activity in the arcuate and paraventricular hypothalamic nuclei is inhibited by anorexigenic agents such as leptin and augmented by the orexigenic agouti-related protein (AGRP) (11).
There is a continuing need in the art to identify and develop more effective drugs with fewer side effects so that patient compliance will increase.